Allogeneic stem cell transplantation is the sole curative treatment for patients with hemoglobinopathies. Widespread implementation of transplant strategies in this group of patients has been severely curtailed, because most patients do not have an HLA identical sibling or unrelated matched donor. An alternative approach which is potentially applicable to most patients with sickle cell anemia is the use of related haploidentical stem cell donors, provided the morbidity and mortality from graft failure and graft versus host disease (GVHD) can be minimized. Conditioning regimens previously utilized to cross the double immunological barrier of host versus graft and graft versus host reactions have been associated with significant life threatening toxicities. This is especially problematic for patients with advanced hemoglobinopathies who have a limited ability to tolerate myeloablative conditioning regimens as a consequence of multi-organ dysfunction and poor performance status. The development of less toxic regimens which would be capable of eliminating host-derived cytotoxic T lymphocyte precursors for cellular resistance to engraftment and minimizing GVHD is key to the successful implementation of a haploidentical transplantation program for patients with hemoglobinopathies. We plan to develop a non-toxic stem cell conditioning regimen especially suited for hemoglobinopathy patients in a non-human primate model which closely mimics the events and difficulties that will be encountered during human stem cell transplantation. The specific aims of the proposal are: 1) To determine whether the use of a purine analogue (fludarabine) as a component of stem cell transplant conditioning regimen will reduce the need for total body irradiation required to achieve long-term engraftment of haploidentical stem cells; 2) To determine whether large doses of purified hematopoietic stem cells (depleted of T cells) will facilitate long-term engraftment in a haploidentical recipient conditioned with a less toxic regimen, and reduce the risk for severe GVHD; 3) To determine whether additional immunosuppressive therapy is capable of further facilitating long-term engraftment of haploidentical donor stem cells and reduce the need for toxic agents in the conditioning regimen. The development of a transplantation regimen that promotes long-term establishment of mixed chimerism without the use of profound myeloablation is expected to lead to access to this curative therapy by a greater number of hemoglobinopathy patients.